A basic principle of pharmaceutical protein formulations is that certain instabilities must be overcome. Degradation pathways of proteins can be separated into two distinct classes, involving chemical instability and physical instability. Chemical instabilities lead to the modification of the protein through bond formation or cleavage. Examples of chemical instability problems include deamidation, racemization, hydrolysis, oxidation, beta elimination and disulfide exchange. Physical instabilities, on the other hand, do not lead to covalent changes in proteins. Rather, they involve changes in the higher order structure (secondary and above) of proteins. These include denaturation, adsorption to surfaces, aggregation and precipitation. Manning et al., Pharm. Res. 6, 903 (1989).
After the discovery of the DNA-structure by Watson and Crick (1953) and the subsequent completion of the human genome sequencing project, the interest in protein chemistry grew very fast. The relationship between genes and their protein products in disease, tissues or development was of particular interest. Next generation pharmaceutical, Issue 6 (GDS publishing Ltd., 2006). Over the intervening decades, the number of protein-based pharmaceuticals increased very fast. Today, certain proteins or peptides can be isolated or synthesized, modified and delivered for easing or healing certain disorders and diseases. The main application pathway for protein-based pharmaceuticals is still the intravenous injection of liquid formulations, but other pathways have also been tested and used.
Many efforts have been made to transfer protein solutions into solid forms. Powdered compositions offer many advantages, e.g., larger amounts of protein can be stored or transported by involving much less space and weight, and energy consumption is lower than that required for cooling the liquid formulations during storage and shipping. Powdered compositions also facilitate new routes of delivery, such as inhalation (Tzannis et al., International Publication No. WO 2005067898), or needle-free injection (Burkoth, The Drug Delivery Companies Report 76-78 (2001)). Several methods have been employed for producing powders from aqueous protein solutions, among them spray drying, spray-freeze drying, freeze drying, or precipitation from supercritical fluids or (partially) organic solutions. Winters et al., Journal of Pharm. Sci. 85(6): 586-594 (1996). In contrast to freeze drying, which is very expensive and time-consuming, spray drying is an effective, efficient means of producing protein-loaded solids that provide opportunities for the development of new delivery forms for biopharmaceuticals, such as inhalation. Maa et al., Pharm. Res. 16(2): 249-254 (1999).
Spray drying a pure protein solution runs the risk of causing partial inactivation, which automatically leads to a lower quality pharmaceutical. Inactivation can, e.g., be caused by process related physical stress due to high temperatures, shear stress and the large phase interface (liquid/gas), such as denaturation or aggregation, or by chemical reactions, e.g., hydrolysis or oxidation.